Background: Zanthoxylum bungeanum Maxim., a traditional Chinese herbal medicine, has been reported to possess therapeutic effects on diseases induced by oxidative stress (DOS), such as atherosclerosis and diabetes complication. However, the active components and their related mechanisms are still not systematically reported.

Objective: The current study was aimed to explore the main active ingredients and their molecular mechanisms of Z. bungeanum for treating DOS using network pharmacology combined with molecular docking simulation.

Methods: The active components of Z. bungeanum pericarps, in addition to the interacting targets, were identified from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. These components were filtered using the parameters of oral bioavailability and drug-likeness, and the targets related to DOS were obtained from the Genecards and OMIM database. Furthermore, the overlapping genes were obtained, and a protein-protein interaction was visualized using the STRING database. Next, the Cytoscape software was employed to build a disease/drug/component/target network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using R software. Finally, the potential active compounds and their related targets were validated using molecular docking technology.

Results: A total of 61 active compounds, 280 intersection genes, and 105 signaling pathways were obtained. Functional enrichment analysis suggested that DOS occurs possibly through the regulation of many biological pathways, such as AGE-RAGE and HIF-1 signaling pathways. Thirty of the identical target genes showed obvious compact relationships with others in the STRING analysis. Three active compounds, quercetin, diosmetin, and beta-sitosterol, interacting with the four key targets, exhibited strong affinities.

Conclusion: The findings of this study not only indicate the main mechanisms involving in oxidative stress-induced diseases but also provide the basis for further research on the active components of Z. bungeanum for treating DOS.